ABSTRACT The disease burden related to type 2-diabetes (T2D) is high and rising worldwide, with the latest estimates showing a global prevalence of 592 million by the year 2035. In the US the estimated cost is of $245 billion and relentlessly increasing. The multifactorial complex etiology of T2D places ?-cell dysfunction as the core of the hyperglycemia, by hindering its functional capability to compensate for the insulin-resistance present in many patients. The predominant objective of our research is to improve our knowledge of the mechanisms of insulin secretion and to identify potential new therapeutic targets to delay or palliate the onset of T2D. The central goal is to define the role of the neuron-specific Cl? extruder KCC2 (Slc12a5) in insulin secretion and glucose homeostasis. Our hypotheses will be tested using mice lacking KCC2 exclusively in ?-cells, their pancreatic islets and insulin-secreting ?-cell lines. Understanding the role that Cl? extruders, loaders and channels play in the physiology of insulin secretion is of capital importance to recognize their role in the pathophysiology of T2D, the most common form of diabetes. Successful completion of our objectives will undoubtedly shed light onto the role that KCC2, Cl? transporters and channels play in the development of diabetes in hereditary and non-hereditary syndromes as well as other diseases associated with them, including cystic fibrosis-related diabetes. This proposal has two specific aims. In Aim 1 we will test the hypothesis that, contrary to the current dogma, KCC2 is functionally expressed in ?-cells and participates in the regulation of insulin secretion. In Aim 2, we will determine if pharmacological inhibition of KCC2 using highly specific compounds that do not cross the blood brain barrier, improve glucose intolerance and/or delay the onset of T2D. The experimental approach to demonstrate our hypotheses is multidisciplinary; it includes comprehensive arrays of metabolic tests in genetically engineered mice and integrative molecular, functional, pharmacological and physiological experiments in vitro.